Apoptosis, or programmed cell death, is a cell process critical for homeostasis, normal development, host defense, and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in many human diseases,(1) including cancer,(1),(3) and it is now recognized that resistance to apoptosis is a hallmark of cancer.(4) As a consequence, targeting of key apoptosis regulators has emerged as an attractive strategy for the development of new approaches to human cancer treatment.(1) 
Most current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, indirectly induce apoptosis in cancer cells. The inability of cancer cells to execute an apoptotic program due to defects in the normal apoptotic machinery is thus often associated with an increase in resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Such primary or acquired resistance of human cancers to current therapies due to apoptosis defects is a major problem in current cancer therapy.
In order to improve survival and quality of life of cancer patients, current and future efforts in the design and development of new molecular target-specific anticancer therapies includes strategies that specifically target cancer cell resistance to apoptosis. In this regard, targeting negative regulators that play a central role in directly inhibiting apoptosis in cancer cells represents a highly promising therapeutic strategy for new anticancer drug design.
One class of central negative regulators of apoptosis is the Inhibitors of Apoptosis Proteins (IAPs). This class includes proteins such as XIAP, cIAP1, cIAP2, ML-IAP, HIAP, KIAP, TSIAP, NAIP, survivin, livin, ILP-2, apollon, and BRUCE. IAP proteins potently suppress cancer cell apoptosis induced by a large variety of apoptotic stimuli, including chemotherapeutic agents, radiation, and immunotherapy.
Although their roles are not limited to regulation of apoptosis,(7),(8) IAP proteins are a class of key apoptosis regulators, and are characterized by the presence of one or more BIR (Baculoviral IAP Repeat) domains.(5)-(6) Among the IAPs, cellular IAP1 (cIAP1) and cIAP2 play a key role in the regulation of death-receptor mediated apoptosis, whereas X-linked IAP (XIAP) inhibits both death-receptor mediated and mitochondria mediated apoptosis by binding to and inhibiting caspase-3/7 and caspase-9, three cysteine proteases critical for execution of apoptosis.(5) These IAP proteins are highly overexpressed both in cancer cell lines and in human tumor tissues and have low expression in normal cells and tissues.(9) Extensive studies have demonstrated that overexpression of IAP proteins make cancer cells resistant to apoptosis induction by a variety of anticancer drugs.(10)-(12) A detailed discussion of IAP proteins and their role is cancer and apoptosis is set forth in U.S. Pat. No. 7,960,372, incorporated herein by reference. Hence, targeting one or more of these IAP proteins is a promising therapeutic strategy for the treatment of human cancer.(10)-(12) 
Studies have shown that peptide-based inhibitors are useful tools to elucidate the anti-apoptotic function of IAPs and the role of IAPs in the response of cancer cells to chemotherapeutic agents. However, peptide-based inhibitors have intrinsic limitations as useful therapeutic agents, including a poor cell permeability and poor in vivo stability. In published studies using Smac-based peptide inhibitors, the peptides had to be fused to carrier peptides to make them relatively cell-permeable.
Small molecule inhibitors of IAP proteins also are known. For example, U.S. Patent Publication Application No. 2005/0197403 and U.S. Pat. No. 7,960,372 disclose dimeric Smac mimetic compounds, each incorporated herein by reference in its entirety.
Despite the discovery of small molecule inhibitors of IAP proteins, the design of potent, non-peptide inhibitors of IAP proteins remains a significant challenge in modern drug discovery. Accordingly, a need still exists in the art for IAP inhibitors having physical and pharmacological properties that permit use of the inhibitors in therapeutic applications. The present invention provides compounds designed to bind to IAP proteins and inhibit IAP protein activity.